This Project of the ICEMR focuses on genetic variation in the malaria parasite and human host, and their impact on malaria transmission and effectiveness of malaria control measures in four sites in Mali, West Africa. Recent advances in genome research provide unprecedented opportunities to tackle questions that decades of immunological research have failed to resolve, such as how people naturally clear malaria parasites from the blood stream or why some people get severe malaria. By investigating how the natural genetic variation in humans and parasites affects malaria susceptibility, and efforts to control malaria, we can build a catalogue of host/parasite molecules that are critical for protective immunity. Recently, Plasmodiun falciparum has developed resistance to the artemisinins, the most effective antimalarial drugs, and the continued evolution of its genome is a major obstacle to malaria control. Now, next generation sequencing approaches coupled with advances in statistics and informatics have transformed our ability to study genetic variation in Plasmodium parasites. These advances are paving the way for large-scale, high-resolution monitoring of genetic variation in malaria parasites. Furthermore, enzymes responsible for the metabolism of antimalarial drugs have been shown to vary in the sequence of the human genes coding for them resulting in varying metabolic efficiency and possible failure of the drug to function accordingly. Apart from the impact of known human genetic polymorphisms related to protection against malaria, novel human gene polymorphisms are as well a major focus of this Project as they may reveal molecular processes that are critical for protective immunity, and will help us to understand the factors that could cause control measures to succeed or fail. Therefore, the goal of this project is to investigate important neglected aspects of malaria immunogenomics at four sites in Mali, representing three major eco-zones that span the sub-Saharan Sahel region. Study sites are already well characterized with respect to parasite populations, seasonal P. falciparum transmission, and malaria epidemiology. This project, which builds on extensive preliminary studies in Mali, includes three specific aims: (1) investigate the genetic diversity of P. falciparum in Malian communities living in different malaria endemic areas, and its relation with disease outcome; (ii) quantify P. falciparum gametocytes using molecular approaches in different epidemiological settings of malaria transmission in Mali, and (iii) assess the host genetic variability and antimalarial molecular markers of resistance in Malian populations living in areas of distinct transmission patterns and compare to parasite genetic diversity.